15,000 Americans die each year from AAA rupture, making it the 13th leading cause of death in this country. Enlargement of AAA is preceded by failure of the elastin and loading of the collagen in the aortic wall. Extracellular matrix (ECM) degeneration continues as the aneurysm enlarges. We have demonstrated that the strength of the AAA wall is also progressively decreased as it enlarges. The AAA will rupture when the strength of the tissue is reduced below the mechanical stress placed on the wall by the intraluminal pressure. Clearly, wall strength and structural integrity play an important role in the natural history of AAA. To understand this natural history, the mechanisms behind wall weakening must first be elucidated. The purpose of the proposed work is to study 2 carefully hypothesized mechanisms of AAA wall weakening by utilizing state-of-the-art, validated bioengineering and biologic methods. Our preliminary work shows that the stress distribution in the AAA wall is quite variable, with regions of high stress concentrations. We have also shown that the commonly found intraluminal thrombus (ILT) within AAA attenuates diffusion of O2 to the AAA wall. A thick layer of ILT may cause hypoxia of the adjacent wall. Our hypothesis is that the strength of the AAA wall is regionally reduced as a direct result of local stress concentrations and this is further augmented by hypoxic conditions. We will address these hypotheses by studying freshly excised AAA tissue from regions with known stress levels and from aneurysms with thick and thin layers of ILT. The microstructure of the tissue will be assessed along with expression of genes related to either degradation or maintenance of wall integrity, such as matrix metalloproteinases and ECM precursors tropoelastin and procollagen. The results of this study could have an immediate impact on the clinical management of AAA. Demonstration that wall strength is reduced by focal concentrations of wall stress or by ILT-induced mural hypoxia would allow clinicians to evaluate AAA in a more biophysically sound manner. Additionally, if the mechanisms behind this weakening are elucidated, therapies may be developed to inhibit or reverse them, leaving an adequately strong, dilated aorta with a reduced risk of rupture.